Deficiency of Gut-Enriched Lipase H Promotes Gut Aging and Reduces Lifespan in Drosophila.

Liph, a gut-enriched Lipase H encoding gene, shows decreased expression during gut aging in both fruit fly and mouse. However, whether such evolutionary conserved Liph plays a protective role in gut aging remains unknown. Here we report that knocking down CG6295, the Drosophila ortholog of the mammalian Liph, led to a shortened lifespan. Loss of CG6295 in adult fly whole body caused impaired gut integrity and function, as well as reduced gut lipid storage in Drosophila. Activation of the Toll/ immune deficiency (Imd) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) immune pathways, and the release of pro-inflammatory cytokine Upd3 (IL-6) indicated immune responses in CG6295 knockdown samples. What's more, knockdown of Drosophila CG6295 specifically in enterocytes (ECs) led to enlarged and flattened ECs, suggesting a potential regulatory mechanism of CG6295 in gut aging. In addition, down-regulation of Liph induced senescence-associated cellular and molecular phenotypes in a rat intestine cell model, suggesting the evolutionary conserved role of Liph in gut aging. Together, we discovered Liph as a novel regulator for gut aging. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43657-024-00187-5.